ACYLAMINOTHIAZOLE DERIVATIVES AND USE THEREOF AS BETA-AMYLOID INHIBITORS

Abstract

The invention relates to a compound having general formula (I), wherein: R1 represents either an optionally-substituted C1-6 alkyl or a C3-7cycloalkyl, a thiophene, a benzothiophene, a pyridinyl, a furanyl or a phenyl, said phenyl groups being optionally substituted; R2 and R'2represent, independently of each other, a hydrogen atom, a halogen atom, a hydroxy, a C1-3 alkoxy, a C1-3 alkyl, a C3-7 cycloalkyl, an O-C(O)-C1-6alkyl group, or R2 and R'2 together form an oxo group; R3 represents either a hydrogen atom or an optionally-substituted C1-6 alkyl; R4 and R5 represent, independently G J of each other, a hydrogen atom, a C1-7 alkyl, ' M (L) a trifluoromethyl, an L group or a Z group; G represents a C1-7 alkyl or a single bond; M represents a C3-7 cycloalkyl, a phenyl, a naphtyl or a pyridinyl, group M being optionally substituted; J represents a hydrogen atom or a group -Y-K; Y represents a single bond, an oxygen atom, a sulphur atom, an optionally-substituted -C1-4alkylene- group, -O-C1-4 alkylene-, -C1-4 alkylene-O- or -N(W); K represents a phenyl or pyridinyl group, group K being optionally substituted, with the proviso that at least one R4 or R5 group represents a Z group; and Z represents a group CN, SO2NR6R7, or a heteroaromatic group, said heteroaromatic group being optionally substituted. The inventive compound takes: the form of a base, an acid addition salt, a hydrate or a solvate. The invention also relates to the use of said compound in therapeutics.

Full Text

ACYLAMINOTHIAZOLE DERIVATIVES AND USE THEREOF AS BETA-
AMYLOID INHIBITORS
The present invention relates to acylamino-
thiazole derivatives, their preparation and their
therapeutic use.
Already known are acylaminothiazole -
derivative compounds which are described in documents
WO03/014095 A and WO2004/033439 A and which inhibit the
formation of the β-amyloid peptide (β-A4).
There still exists a need to find and to develop
products which inhibit the formation of the p-amyloid
peptide (β-A4). The compounds of the invention respond
to this aim.
The present invention first provides
compounds conforming to the general formula (I):

in which
R1 represents either a C1-6 alkyl optionally substituted
by one to three substituents selected from a halogen, a
trifluoromethyl, a hydroxyl, a C1-6 alkoxy, a C1-6
thioalkyl, a thiophene or a phenyl; or a C3-7 cycloalkyl,
a thiophene, a benzothiophene, a pyridinyl, a furanyl
or a phenyl; the said phenyl groups being optionally
substituted by one to three substituents selected from
a halogen atom, a C1-6 alkyl, a C1-6 alkoxy, a hydroxyl,

a methylenedioxy, a phenoxy, a benzyloxy or a
trifluoromethyl;
R2 and R'2 represent independently of one another a
hydrogen atom, a halogen atom, a hydroxyl, a C1-3
alkoxy, a C1-3 alkyl, a C3-7 cycloalkyl or an O-C(O)-C1-6
alkyl group, or R2 and R2 together form an oxo group;
R3 represents either a hydrogen atom or a C1-6 alkyl
optionally substituted by a hydroxyl, a C1-6 cycloalkyl
or a C1-3 alkoxy;
R4 and R5 represent independently of one another a
hydrogen atom, a C1-7 alkyl, a trifluoromethyl, a group
L or a group Z;

G represents a C1-7 alkyl or a single bond;
M represents a C3-7 cycloalkyl, a phenyl, a naphthyl or
a pyridinyl, the group M being optionally substituted
by one or more groups selected from a halogen atom, a
hydroxyl group, a C1-3 alkyl, a C1-3 alkoxy, a
trifluoromethyl, a trifluoromethoxy and a -O-CHF2;
J represents a hydrogen atom or a group -Y-K;
Y represents a single bond, an oxygen or sulphur atom,
a -C1-4 alkylene-, -O-C1-4 alkylene- or -C1-4 alkylene-O-
group or a group -N(W)-, the -C1-4 alkylene- group being
optionally substituted by a hydroxyl or C1-3 alkoxy
group;
W represents either a hydrogen atom, or a C1-3 alkyl
optionally substituted by a phenyl, or a phenyl;

K represents a phenyl or pyridinyl group, the group K
being optionally substituted by one or more groups
selected from a halogen atom, a hydroxyl group, a C1-3
alkyl, a C1-3 alkoxy, a trifluoromethyl, a trifluoro-
methoxy and an -O-CHF2;
with the proviso that at least one group R4 or R5
represents a group Z;
Z represents a CN group, a group S02NR6R*7 or a
heteroaromatic group; the said heteroaromatic group
being optionally substituted by a group R8; Ra
representing either a C1-4 alkyl which is itself
optionally substituted by a CN, a phenyl or a phenoxy;
or a phenyl; the said phenyl and phenoxy groups being
optionally substituted by 1 to 3 groups selected from a
halogen atom, a C1-3 alkyl, a C1-3 alkoxy and a
trifluoromethyl;
R6 and R*7 represent, independently of one another,
either a hydrogen atom, or a C1-6 alkyl group optionally
substituted by a C3-7 cycloalkyl, a C3-7 cycloalkenyl,
C1-3 alkoxy, a phenyl, a naphthalenyl, a morpholinyl or
a pyridinyl; or a C3-7 cycloalkyl, C1-6 alkoxy, a phenyl
or an indanyl; the said C3-7 cycloalkyl, C3-7
cycloalkenyl, phenyl, naphthalenyl, morpholinyl,
pyridinyl and indanyl groups being optionally
substituted by one or two groups selected from a C1-3
alkyl, a hydroxyl, a C1-3 alkoxy, a phenyl or a halogen
atom; or

R6 and R*7 with the nitrogen atom which carries them form
an aziridine, azetidine, pyrrolidine, piperidine,
morpholine or benzopiperidine ring.
Among the compounds of general formula (I) a
first subgroup of compounds is composed of the
compounds for which:
R1 represents a C1-6 alkyl or a phenyl which is
optionally substituted by 1 to 3 halogen atoms; and/or
R2 and R'2 represent independently of one another a
hydrogen atom or a hydroxyl; and/or
R3 represents a C1-6 alkyl; and/or
R4 and R5 represent independently of one another a
hydrogen atom, a C1-7 alkyl, a trifluoromethyl, a group
L or a group Z;
G represents a C1-7 alkyl or a single bond; and/or
M represents a phenyl which is optionally substituted
by one or more halogen atoms; and/or
J represents a hydrogen atom or a group -Y-K; and/or
Y represents a single bond, an oxygen atom or
-O-C1-4 alkylene-; and/or
K represents a phenyl group which is optionally
substituted by one or more groups selected from a
halogen atom, a C1-3 alkyl and a trifluoromethyl;
with the proviso that at least one group R4 or R5
represents a group Z; and/or

Z represents a CN group, a group S02NR6R*7 or a hetero-
aromatic group; the said heteroaromatic group being
optionally substituted by a group Rs; Rs representing
either a C1-4 alkyl which is itself optionally
substituted by a phenyl; or a phenyl; and/or
R6 and R*7 represent, independently of one another,
either a hydrogen atom, or a C1-6 alkyl group optionally
substituted by a phenyl or by a naphthalenyl; or a
phenyl or an indanyl; the said phenyl groups being
optionally substituted by one or two groups selected
from a C1-3 alkoxy, a phenyl or a halogen atom; or
R6 and R7, with the nitrogen atom which carries them,
form a benzopiperidine ring.
The compounds for which simultaneously R1 R2,
R'2, R3, R4, R5, G, M, J, Y, K, Z, R6, R*7 and R8 are as
defined in the first subgroup of compounds above form a
second subgroup.
Among the compounds of general formula (I)
and the subgroups above, a third subgroup of compounds
is composed of the compounds for which:
R1 represents a C1-4 alkyl, preferably an isopropyl or a
tert-butyl, or a phenyl substituted by two fluorine
atoms; and/or
R2 and R'2 represent independently of one another a
hydrogen atom or a hydroxyl; and/or
R3 represents a C1-4 alkyl, preferably a methyl, ethyl or
propyl.
In the context of the present invention:

- Ct-z , where t and z may take the values from 1 to 7,
is understood to mean a carbon chain which can have
from t to z carbon atoms, for example, C1-3, a carbon
chain which can have from 1 to 3 carbon atoms, C3-6, a
carbon chain which can have from 3 to 6 carbon atoms;
and so on;
- alkyl is understood to mean a linear or branched
saturated aliphatic group: for example, a C1-6 alkyl
group represents a linear or branched carbon chain of
from 1 to 6 carbon atoms, more particularly a methyl,
ethyl, propyl, 1-methylethyl, butyl, isobutyl, sec-
butyl, tert-butyl, and so on, preferably a methyl,
ethyl, propyl or 1-methylethyl;
- alkylene is understood to mean a linear or branched
saturated divalent alkyl group: for example, a C1-3
alkylene group represents a divalent carbon chain of
from 1 to 3 carbon atoms which is linear or branched,
more particularly a methylene, ethylene, isopropylene
or propylene;

- cycloalkyl is understood to mean a cyclic alkyl
group: for example, a C3-7 cycloalkyl group represents a
cyclical carbon chain of from 3 to 7 carbon atoms, more
particularly a cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl or cycloheptyl, preferably a cyclopentyl or
cyclohexyl;
- cycloalkenyl is understood to mean a mono- or
polyunsaturated cyclic alkyl group: for example, a C3-7
cycloalkenyl group represents a mono- or polyunsaturated

cyclical carbon chain of from 3 to 7 carbon atoms, more
particularly a cyclopropenyl, cyclobutenyl, cyclo-
pentenyl, cyclohexenyl or cycloheptenyl, preferably a
cyclopentenyl or cyclohexenyl;
- thioalkyl is understood to mean an S-alkyl group
having a linear or branched, saturated aliphatic chain;
- alkoxy is understood to mean an O-alkyl group having
a linear or branched, saturated aliphatic chain;
- halogen atom is understood to mean a fluorine, a
chlorine, a bromine or an iodine;
- "R2 and R'2 together form an oxo group" is intended to
mean the group such that:

- heteroaromatic group is understood to mean a cyclic
aromatic group containing between 1 and 10 carbon atoms
and between 1 and 4 heteroatoms, such as nitrogen,
oxygen or sulphur. Examples that may be mentioned of
heteroaromatic groups include oxazolyl, oxadiazolyl,
tetrazolyl and benzoxazolyl groups, etc.
The compounds of general formula (I) may
include one or more asymmetric carbons. They may
therefore exist in the form of enantiomers or diastereo-
isomers. These enantiomers and diastereoisomers, and
their mixtures, including the racemic mixtures, form
part of the invention. When the carbon carrying R2 and
R'2 and/or the carbon carrying R3 are asymmetric,

preference is given to the compounds of general formula
(I) for which the carbon carrying R2 and R'2 is of (S)
configuration and/or the carbon carrying R3 is of (S)
configuration.
The compounds of formula (I) may exist in the form of
bases or of addition salts with acids. Such addition
salts form part of the invention.
These salts are advantageously prepared with
pharmaceutically acceptable acids, although the salts
of other acids useful, for example, for the purification
or isolation of compounds of formula (I) also form part
of the invention.
The compounds of general formula (I) may
occur in the form of hydrates or solvates, in other
words in the form of associations or combinations with
one or more molecules of water or with a solvent. Such
hydrates and solvates likewise form part of the
invention.
The present invention secondly provides processes for
preparing the compounds of formula (I).
Thus these compounds may be prepared by
processes, illustrated in the schemes below, whose
operating conditions are conventional for the person
skilled in the art.
A protective group is understood to mean a group which
makes it possible to block the reactivity of a
functional group or position in the course of a
chemical reaction which might affect it, and which

restores the molecule after cleavage according to
methods known to the person skilled in the art.
Examples of protective groups and of methods of
protection and deprotection are given, inter alia, in
Protective groups in Organic Synthesis, Greene et al.,
2nd Ed. (John Wiley & Sons, Inc., New York).
The meanings of R1 R2, R'2/ R3, R4/ R5/ G, M, J, Y, K,
Z, R6, R*7 and R8 in the compounds of formula (II) to
(XXI) below are as defined for the compounds of formula
(I), unless any other definition is specified.
According to Scheme 1 below, the compound of
formula (I) may be obtained by peptide coupling of the
2-aminothiazole of formula (III) with the acylamino
acid of formula (II) according to conditions which are
known to the person skilled in the art: for example, in
the presence of benzotriazol-1-yloxytris(pyrrolidino)-
phosphonium hexafluorophosphate (PyBOP) or of benzo-
triazol-1-yloxytris(dimethylamino)phosphonium hexa-
fluorophosphate (BOP) and of N-ethylmorpholine or
N-methylmorpholine in an inert solvent such as
N,N-dimethylformamide, acetonitrile or dichloromethane
at a temperature which may range from 0°C to the
ambient temperature.
The compound of formula (II) may be obtained by peptide
coupling of the compound of formula (IV) with the
protected acid of formula (V), in which Pg represents a
protective group, for example a benzyl, according to

methods which are known to the person skilled in the
art, as described above.
The compound thus obtained is subsequently deprotected.
Where the protection is a benzyl the compound is
hydrogenated beforehand in the presence of palladium on
carbon in absolute ethanol at atmospheric hydrogen
pressure, at ambient temperature, to give the compound
of formula (II).

Alternatively, the compound of formula (I)
may be prepared according to Scheme 2 below.
According to Scheme 2 the compound of formula
(I) may be obtained by peptide coupling of the compound
of formula (IV) with the amine of formula (VI),
according to methods which are known to the person
skilled in the art, such as, for example, in the
presence of hydroxybenzotriazole hydrate (HOBt) and of
l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydro-
chloride (EDAC HC1).

The compound of formula (VI) may be obtained
by peptide coupling of the 2-aminothiazole of formula
(III) with the protected amine of formula (VII), in

which Pg represents a protective group, for example an
N-tert-butoxycarbony1 (Boc), according to methods which
are known to the person skilled in the art, as
described above. The compound thus obtained is
subsequently deprotected. Where the protection is a Boc
the deprotection is accomplished by acidic hydrolysis
in the presence of gaseous hydrochloric acid in
solution in an anhydrous solvent or of trifluoroacetic
acid, to give the compound of formula (VI).
The compounds of formula (I) in which R2 and R'2 form an
oxo group may be obtained by oxidizing a hydroxyl of
the compound of formula (I) in which R2 or R'2
represents a hydroxyl group. The reaction may be
carried out according to the conditions which are known
to the person skilled in the art, for example with the
Dess Martin reagent. These compounds may also be
obtained by direct coupling of a keto acid of formula
(IV), in which R2 and R'2 together form an oxo group,
with an amine of formula (VI) according to the
conditions which are known to the person skilled in the
art. The methods of preparing such keto acids are known
to the person skilled in the art.
The compounds of formula (III) in which R4 or
R5 = Z, where Z represents a CN group or a group of
heteroaromatic type, may be prepared in accordance with
Schemes 3 to 6 below.
The compounds of general formula (IIIa) and
(IIIb), i.e. the compounds of general formula (III) in

which R4 or R5 represents an oxadiazole group, may be
obtained according to the methods illustrated by-
Schemes 3 and 4 below.

According to Scheme 3 above, the compound of
formula (IIIa) may be obtained by reacting the compound
of formula (VIII) , in which R represents a C1-6 alkoxy
group and Pg represents a protective group such as a
tert-butoxycarbonyl group (Boc), with an amide oxime of
formula H2NC(=NOH)R8 in anhydrous tetrahydrofuran at
reflux in the presence of sodium hydride and of 4A
molecular sieve in powder form. The compound thus
obtained is subsequently deprotected according to the
conditions which are known to the person skilled in the
art.
According to Scheme 4 below, the compound of
formula (X) is obtained by peptide coupling of the
compound of formula (IX), in which Pg represents a
protective group such as a Boc, with ammonia, in the

presence for example of HOBt and of EDAC HCl. The
compound of formula (X) may subsequently be reacted
with trifluoroacetic anhydride (TFAA) in the presence
of a base, for example triethylamine, to give the
compound of formula (XI).

The compound of formula (XII) may be obtained
by addition of hydroxylamine HCl to the compound of
formula (XI) in the presence of a base, for example
sodium methoxide, according to an adaptation of the
process described by Moloney et al. (J. Chem. Soc.

Perkin Trans I, 1999, p. 2725). The compound of formula
(XII) may subsequently be cyclized in the presence of a
base such as sodium hydride and of an ester of formula
R8CO2CH3 or R8CO2C2H5. The compound thus obtained is
deprotected according to the conditions which are known
to the person skilled in the art, to give the compound
of general formula (IIIb).
The method of preparation described in
Scheme 4 may also make it possible to prepare the
compounds of general formula (IIIc), i.e. the compounds
of general formula (III) in which R4 or R5 represents a
-CN group, by deprotecting the compounds of formula
(XI) according to the conditions which are known to the
person skilled in the art.
The compounds of general formula (IIId), i.e.
the compounds of general formula (III) in which R4 or R5
represents a benzoxazole group, may be obtained
according to the method illustrated by Scheme 5 below.

According to Scheme 5 the compound of formula
(IIId) may be obtained by a peptide coupling of the
compound of formula (IX) as defined above and of a
compound of formula (XIII), according to the conditions
which are known to the person skilled in the art, for
example in the presence of benzotriazol-1-yloxytris-
(pyrrolidino)phosphonium hexafluorophosphate (PyBOP) or
of benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate (BOP) and of N-ethylmorpholine or

N-methylmorpholine in an inert solvent such as
N,N-dimethylformamide at a temperature which may range
from 0°C to the ambient temperature.
The compounds thus obtained may subsequently be
cyclized by a Mitsunobu reaction according to an
adaptation of the process described by Wang et al.
(Tetrahedron Letters, 1997, p. 6529) and then
deprotected by the methods which are known to the
person skilled in the art, to give the compound of
general formula (IIId).

The compounds of general formula (IIIe), i.e.
the compounds of general formula (III) in which R4 or R5

represents a tetrazole group, may be obtained according
to the method illustrated by Scheme 6 above.
According to Scheme 6 the compound of formula (XIV) may
be obtained by peptide coupling of the compound of
formula (IX) as defined above and of a primary amine of
formula R8NH2 according to the conditions which are
known to the person skilled in the art, for example in
the presence of HOBt and EDAC HC1. The compound (XIV)
thus obtained is subjected to a Mitsunobu reaction
according to the conditions which are known to the
person skilled in the art, for example in the presence
of triphenylphosphine, diisopropyl azodicarboxylate
(DIAD) and azidotrimethylsilane (TMSN3) , according to an
adaptation of the process described by De Lombaert et
al. in J. Med. Chem. 2000, p. 488. The compound
obtained is subsequently deprotected by the methods
which are known to the person skilled in the art, to
give the compound of general formula (IIIe).
The compounds of general formula (III) in
which R4 or Rs represents an oxazole group may be
obtained starting from the corresponding aldehyde,
which is itself prepared starting from the ester of
formula (VIII), according to procedures which are known
to the person skilled in the art, for example with
p-toluenesulphonylmethyl isocyanate in the presence of
a base, such as potassium carbonate or sodium
methoxide, according to an adaptation of the method

described by van Leusen et al. (Tetrahedron Letters,
1972, p. 2369).
The compound of formula (VIII), as defined
above, may be obtained by protecting a compound of
formula (IIIo),

for example, when Pg represents a Boc group, by the
action of di-tert-butyl dicarbonate in anhydrous
tetrahydrofuran in the presence of dimethylaminopyridine
at ambient temperature.
The compound of formula (IX), as defined above, may be
obtained by hydrolysing the ester function of the
corresponding compound of formula (VIII) according to
conditions which are known to the person skilled in the
art, for example with lithium hydroxide in a 7:3 (v/v)
tetrahydrofuran/water mixture at a temperature of 60°C.
The compounds of formula (IIIo) may be
prepared according to the methods which are illustrated
by Schemes 7 and 8 below.
The compound of formula (IIIo) in which R4 = -C(O)R, R
representing a C1-6 alkoxy group, may be obtained
according to Scheme 7 below.

According to Scheme 7 the compound of formula
(IIIo) may be obtained by reacting an aldehyde of
formula (XV) with the dichloromethyl acetate of formula
Cl2CHCOR, in which R represents a C1-6 alkoxy, and, for
example, sodium methoxide or ethoxide at 0°C according
to an adaptation of the process described by Takeda
(Bull. Chem. Soc. JP, 1970, p. 2997). The mixture of
products (XVI) and (XVII) obtained is treated with
thiourea in the presence for example of methanol or
ethanol at reflux for 4 or 8 hours to give the compound
of formula (IIIo).
The compound of formula (IIIo) in which R5 = -C(O)R, R
representing a C1-6 alkoxy group, may be obtained
according to Scheme 8.

According to Scheme 8 the compound of formula
(IIIo) may be obtained by brominating a p-keto ester of
formula (XX) , in which R represents a C1-6 alkoxy,
followed by a reaction with thiourea on the compound
(XXI) thus obtained, according to an adaptation of the
process described by A. Barton et al. (J.C.S. Perkin I,
1982, p. 159).
The β-keto ester of formula (XX) may be obtained by
reacting a ketone of formula (XVIII) with a dialkyl
carbonate of formula CO(R)2 in which R represents a C1-6
alkoxy group, according to an adaptation of the process
described by L. Crombie et al. (J.C.S. Perkin Trans. I,
1987, p. 323) . The p-keto ester of formula (XX) may
also be obtained by reacting an acid of formula (XIX),
activated with carbonyldiimidazole (CDI) with a
malonate of formula RCOCH2CO2K, in which R represents a
C1-6 alkoxy, according to an adaptation of the process
described for example by D.W. Brooks et al. (Angew.
Chem. Int. Ed., 1979, p. 72).
Where R4 represents a hydrogen atom the preparation of
the compound of formula (XX) is accomplished according
to an adaptation of the process described for example
by R. Zhao et al. in Tetrahedron Letters, 2001,
p. 2101.
The compounds of formula (III) in which R4 or
R5 = Z, where Z represents a group S02NRsR*7, may be
prepared starting from the corresponding sulphonyl

chlorides, which are available commercially, or
starting from compounds described in the literature
(for example by R.P. Fatheree et al. in WO 99/26932A1,
by I.T. Barnish et al. in J. Med. Chem., 1980, p. 117
and by R. Fischer et al. in WO 01/047904A1), or may be
prepared by methods which are described therein or
which are known to the person skilled in the art.
In Schemes 1 to 8 the starting compounds and
the reagents, especially the compounds of formula
(III), (IV), (V), (VII), (VIII), (IX), (XIII), (XV),
(XVIII), (XIX), CO(R)2, RC (O) CH2CO2K, C12CHCOR, R8NH2,
R8CO2CH3, R8CO2C2H5 and H2NC (=N0H) R8/ when the method of
preparing them is not described, are available
commercially or are described in the literature, or may
be prepared by methods which are described therein or
which are known to the person skilled in the art.
For example, the compounds of formula (IV) where R2 or
R'2 represents a hydroxyl may be prepared by addition of
trimethylsilyl cyanide to an aldehyde according to an
adaptation of the process described by D.A. Evans et
al. (J.C.S., Chem. Comm. 1973, p. 55) or by the action
of sodium nitrite on an alpha-amino acid according to
an adaptation of the process described by I. Shinn et
al. (J. Org. Chem., 2000, p. 7667).
For example, the amide oxime of the formula H2NC(=NOH)R8
may be obtained according to processes which are known
to the person skilled in the art, for example according

to the method described by Moloney et al. in J. Chem.
Soc. Perkin Trans. I, 1999, p. 2725.
When a functional group of a compound is
reactive, for example when R1 comprises a hydroxyl, it
may necessitate prior protection before reaction. The
person skilled in the art will be able readily to
determine the necessity of a prior protection.
The following examples describe the
preparation of certain compounds in accordance with the
invention. These examples are not limitative and merely
illustrate the invention.
The numbers of the compounds exemplified refer to those
given in the table thereafter. The elemental micro-
analyses and the NMR, IR or LC-MS (liquid chromatography
coupled to mass spectrometry) analyses confirm the
structures of the compounds obtained.
Example 1:
2-{2-(S)-[2-(S)-hydroxy(3-methyl)butyrylamino]-
pentanoyl}amino-5-(l-methylethyl-4-(3-phenyl-
1,2,4-oxadiazol-5-yl)thiazole (compound 8)

Example 1.1:
methyl 2-amino-5-(1-methylethyl)thiazole-4-carboxylate

14.4 g of isobutyraldehyde in solution in
400 ml of diethyl ether are admixed at 0°C with 24.6 g
of methyl dichioroacetate and then, dropwise, with
400 ml of a solution of sodium methoxide (0.5 M) in
methanol. After 1 h at 0°C 100 ml of saturated aqueous
sodium chloride solution are added and the mixture is
extracted with ether. The organic phase is dried over
anhydrous sodium sulphate. Solely the ether is
evaporated, retaining the methanol, 8 g of thiourea are
added and the mixture is heated at reflux for 6 hours.
The reaction mixture is evaporated to dryness and a
residue is taken up in ethyl acetate and washed with
10% aqueous ammonium hydroxide solution and then with
saturated aqueous sodium chloride solution. The organic
phase is dried over anhydrous sodium sulphate and then
concentrated. The residue is taken up in 100 ml of
ether and filtered on a frit. This gives 18.6 g of a
white solid.
NMR 300 MHz (CDCl3) δ ppm: 1.25 (d, 6H) ; 3.35 (s,3H);
4.10 (m,1H); 5.50 (s,2H).

5.81 g of methyl 2-amino-5-(1-methylethyl)-
thiazole-4-carboxylate, obtained in step 1.1, in
solution in 3 00 ml of tetrahydrofuran are admixed with
6.96 g of di-tert-butyl dicarbonate and 0.177 g of
dimethylaminopyridine. The mixture is stirred at
ambient temperature for 16 h. The reaction mixture is
evaporated. The residue is taken up in ethyl acetate
and washed twice with 0.5 N aqueous hydrochloric acid
solution, once with water and then with saturated
aqueous sodium chloride solution. The organic phase is
dried over anhydrous sodium sulphate and concentrated.
This gives 8.35 g of the protected aminothiazole
derivative, in the form of a solid which is used as it
is without purification.
LC/MS: MH+ = 401 (M - Boc)+ = 301

Example 1.3:
2-amino-5-(1-methylethyl)-4-(3-phenyl-1,2,4-oxadiazol-
5-yl)thiazole
2.9 g of benzamide oxime in solution in
150 ml of tetrahydrofuran are admixed slowly at ambient
temperature with 0.96 g of sodium hydride and 2 g of 4A
molecular sieve. The mixture is heated at 60°C for 1 h
30 min. The mixture is allowed to return to ambient
temperature and then 3.6 g of methyl 2-tert-butoxy-
carbonylamino-5-(1-methylethyl)thiazole-4-carboxylate,
obtained in step 1.2, in 3 0 ml of tetrahydrofuran are
added. The reaction mixture is heated at 60°C for
12 hours. The reaction is terminated by adding water.
The molecular sieve is filtered off and then the
solution is concentrated. The product is taken up in
ethyl acetate. Evaporation to dryness gives 3.4 g of a
white solid.
3.4 g of the product obtained above in solution in
60 ml of trifluoroacetic acid are stirred at ambient
temperature for 30 minutes and then evaporated. The
residue is taken up in ethyl acetate and washed twice
with saturated aqueous sodium carbonate solution and

1.77 g of 2-amino-5-(1-methylethyl)-
4-(3-phenyl-1,2,4-oxadizaol-5-yl)thiazole, obtained in
step 1.3, in solution in 50 ml of dimethylformamide at
0°C are admixed with 0.75 ml of N-methylmorpholine,
3.5 g of PyBOP and then 1.5 g of (S)-Bocnorvaline. The
reaction mixture is allowed to return to ambient
temperature and then is stirred for 16 h. Following
evaporation the residue is taken up in ethyl acetate
and washed twice with saturated aqueous sodium
bicarbonate solution, twice with water, once with a 1H
aqueous solution of potassium hydrogen sulphate and
then with saturated aqueous sodium chloride solution.
The organic phase is dried over anhydrous sodium
sulphate and then concentrated. The residue is

chromatographed on a silica gel column, eluting with a
95:5 (v/v) mixture of dichloromethane and ethyl
acetate. This gives 1.4 g of a white solid.
1.4 g of the product obtained above, in solution in
60 ml of trifluoroacetic acid, are stirred at ambient
temperature for 3 0 min and then evaporated. The residue
is taken up in ethyl acetate and washed twice with
saturated aqueous sodium carbonate solution and then
with saturated aqueous sodium chloride solution. The
organic phase is dried over anhydrous sodium sulphate
and then evaporated, to give 1 g of a white solid.
NMR 300 MHz (CDCl3) δ ppm: 0.98 (t,3H); 1.45 (d,6H);
1.62 (m,2H); 1.92 (m,2H); 3.64 (m,1H); 4.25 (m,1H);
7.50 (m,3H); 8.20 (m,2H).
Example 1.5:
2-{2-(S)-[2-(S)-hydroxy(3-methyl)butyrylamino]-
pentanoyl}amino-5-(l-methylethyl-4-(3-phenyl-
1,2,4-oxadiazol-5-yl)thiazole
0.2 g of 2-[2-(S)-pentanoylamino]amino-
5-(1-methylethyl)-4-(3-phenyl-1,2,4-oxadiazol-5-yl)-
thiazole, obtained in step 1.4, in solution in 10 ml of
dimethylformamide at 0°C is admixed with 0.06 ml of
N-methylmorpholine, 0.30 g of PyBOP and then 0.06 g of
a-hydroxyhydrovaleric acid. The reaction mixture is
allowed to return to ambient temperature and is stirred
for 18 h. The reaction mixture is evaporated. The
residue is taken up in ethyl acetate and washed twice

with saturated aqueous sodium bicarbonate solution,
twice with water, once with a 1 M aqueous solution of
potassium hydrogen sulphate and then with saturated
aqueous sodium chloride solution. The organic phase is
dried over anhydrous sodium sulphate and then
concentrated. The residue is chromatographed on a
silica column, eluting with a 95:5 (v/v)
dichloromethane/ethyl acetate mixture, to give 0.15 g
of a white solid.
LC/MS: MH+ = 486
NMR: described in the table below, (compound 8)
Example 2:
2-{2-(S)-[2-(S)-hydroxy(3,3-dimethyl)butyrylamino]-
pentanoyl}amino-5-(2-benzyloxy)phenylthiazole 4-nitrile

Example 2.1:
methyl 2-amino-5-(2-benzyloxy)phenylthiazole
4-carboxylate
The procedure is the same as in step 1.1 of
Example 1, replacing the isobutyraldehyde by
2-benzyloxybenzaldehyde (42.25 g) in solution in 400 ml
of diethyl ether, to which, at 0°C, 25.7 g of methyl
dichloroacetate and then, dropwise, 400 ml of a 0.5 M
solution of sodium methoxide in methanol are added.
After 1 h at 0°C 100 ml of saturated aqueous sodium
chloride solution are added and the mixture is
extracted with ether. Treatment with thiourea (10.66 g)
gives 19 g of a yellow solid.
LC/MS: MH+ =341
Example 2.2:
methyl 2-tert-butoxycarbonylamino-5-(2-benzyloxy)phenyl-
thiazole-4-carboxylate

15.7 g of methyl 2-amino-5-(2-benzyloxy)-
phenylthiazole-4-carboxylate, obtained in step 2.1, in
solution in 3 00 ml of tetrahydrofuran are admixed with
11.5 g of di-tert-butyl dicarbonate and 0.4 g of
dimethylaminopyridine. The mixture is stirred at
ambient temperature for 16 h. The reaction mixture is
evaporated. The residue is taken up in ethyl acetate
and washed twice with a 0.5 N aqueous hydrochloric acid
solution, once with water and then with an aqueous
saturated sodium chloride solution. The organic phase
is dried over anhydrous sodium sulphate and
concentrated. This gives 20.5 g of the protected
aminothiazole derivative in the form of a solid, which
is used as it is without purification.
LC/MS: MH+ = 441 (M - Boc)+ = 341

5.6 g of methyl 2-tert-butoxycarbonylamino-
5-(2-benzyloxy)phenylthiazole-4-carboxylate, obtained
in step 2.2, in solution in 150 ml of tetrahydrofuran
are admixed at ambient temperature with a solution of
1.35 g of lithium hydroxide in 80 ml of distilled
water. The reaction mixture is heated at tetrahydrofuran
reflux for 16 h and then concentrated. The residue is
taken up in water and washed twice with ethyl acetate.
The aqueous phase is acidified with 1 N hydrochloric
acid solution to a pH ~ 4, saturated with sodium
chloride and extracted twice with ethyl acetate. The
organic phase is dried over anhydrous sodium sulphate
and then concentrated.
LC/MS: MH+ = 427

Example 2.4:
2-tert-butoxycarbonylamino-5-(2-benzyloxy)phenyl-
thiazole 4-amide
4.2 g of 2-tert-butoxycarbonylamino-
5-(2-benzyloxy)phenylthiazole-4-carboxylic acid,
obtained in step 2.3, in solution in 150 ml of
dimethoxyethane at 0°C are admixed with 1.3 g of
N-methylmorpholine and then 1.7 g of isobutyl
chloroformate and 8 ml of 25% ammonium hydroxide
solution. The reaction mixture is stirred at ambient
temperature for 16 h and then concentrated. The residue
is taken up in ethyl acetate and washed twice with a
1 M aqueous solution of potassium hydrogen sulphate,
once with water and then with saturated aqueous sodium
chloride solution. The organic phase is dried over
anhydrous sulphate and concentrated. The residue is
chromatographed on a silica column, eluting with an
80/20 (v/v) dichloromethane/ethyl acetate mixture, to
give 3.3 g of a white solid.
LC/MS: MH+ = 42 6

Example 2.5:
2-tert-butoxycarbonylamino-5-(2-benzyloxy)phenylthiazole
4-nitrile
3.3 g of 2-tert-butoxycarbonylamino-
5-(2-benzyloxy)phenylthiazole 4-amide, obtained in step
2.4, at 0°C in 80 ml of dichloromethane are admixed
with 2.6 ml of triethylamine and 1.7 ml of
trifluoroacetic anhydride. The mixture is stirred at
0°C for one hour and then at ambient temperature for
12 hours, and then concentrated. The residue is
extracted with dichloromethane and washed twice with a
1 M aqueous solution of potassium hydrogen sulphate and
then with saturated aqueous sodium chloride solution.
The organic phase is dried over anhydrous sodium
sulphate and then concentrated. This gives 1.1 g of a
yellow solid.
LC/MS: MH+ = 408
NMR 300 MHz (CDCl3) δ ppm: 1.55 (s,9H); 5.22 (s,2H);
7.0O-7.80 (m,9H).

Example 2.6:
2-{2-(S)-[2-(S)-hydroxy(3,3-dimethyl)butyrylamino]-
pentanoyl}amino-5-(2-benzyloxy)phenylthiazole 4-nitrile
The compound obtained in step 2.5 is
subsequently deprotected with trifluoroacetic acid as
described in step 1.3 of Example 1, then 2 successive
couplings are carried out according to the processes
described in steps 1.4 and 1.5 of Example 1.
This gives 0.1 g of end product.
NMR: described in the table below, (compound 22)
Example 3:
2-{2-(S)-[2-(S)-hydroxy(3,3-dimethyl)butyrylamino]-
pentanoyl}amino-5-(2-benzyloxy)phenyl-4-(5-methyl-
1,2,4-oxadiazol-3-yl)thiazole (compound 13)

Example 3.1:
2-tert-butoxycarbonylamino-5-(2-benzyloxy)phenylthiazole
4-amide oxime
4 ml of a 0.5 M solution of sodium methoxide
in methanol are admixed dropwise with 0.136 g of
hydroxylamine in methanol. A white precipitate is
formed and the reaction mixture is stirred at ambient
temperature for one hour and then admixed with 0.8 g of
the compound 2-tert-butoxycarbonylamino-5-(2-benzyloxy)-
phenylthiazole 4-nitrile obtained in step 2.5 of
Example 2. The mixture is heated for 15 hours and then
the methanol is evaporated. The residue is extracted in
ethyl acetate and washed twice with saturated aqueous
sodium chloride solution. The organic phase is dried
over anhydrous sodium sulphate and then concentrated.
This gives 0.67 g of a solid.
LC/MS: MH+ = 441

Example 3.2:
2-tert-butoxycarbonylamino-5-(2-benzyloxy)phenyl-
4-(5-methyl-1,2#4-oxadiazol-3-yl) thiazole
0.66 g of 2-tert-butoxycarbonylamino-
5-(2-benzyloxy)phenylthiazole 4-amide oxime, obtained
in step 3.1, in solution in 3 0 ml of tetrahydrofuran is
admixed at ambient temperature slowly with 0.75 g of
sodium hydride and 0.5 g of 4A molecular sieve. The
mixture is heated at 60°C for 1 h 3 0 min and then
220 µl of ethyl acetate are added and heating at 60°C
is continued for 12 h. The reaction is terminated by
adding water. The molecular sieve is filtered off and
the solution is concentrated. The product is taken up
in ethyl acetate. Evaporation to dryness gives 0.58 g
of a white solid.
NMR 300 MHz (CDCl3) δ ppm: 1.53 (s,9H); 2.48 (s,3H);
5.04 (s,2H); 6.9O-7.42 (m,9H); 8.00 (s,1H).

0.58 g of 2-tert-butoxycarbonylamino-
5-(2-benzyloxy)phenyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)-
thiazole, obtained in step 3.2, in solution in 30 ml of
trifluoroacetic acid is stirred at ambient temperature
for 30 min and then evaporated. The residue is taken up
in ethyl acetate and washed twice with saturated
aqueous sodium carbonate solution and then with
saturated aqueous sodium chloride solution. The organic
phase is dried over anhydrous sodium sulphate and then
evaporated, to give 0.46 g of a white solid.
NMR 300 MHz (CDCl3) δ ppm: 2.54 (s,3H); 5.07 (s,2H);
6.98-7.48 (m,9H).

Example 3.4:
2-{2-(S)-[2-(S)-hydroxy(3,3-dimethyl)butyrylamino]-
pentanoyl}amino-5-(2-benzyloxy)phenyl-4-(5-methyl-
1,2,4-oxadiazol-3-yl)thiazole
Two successive couplings are carried out
according to the processes described in steps 1.4 and
1.5 of Example 1.
This gives 0.270 g of end product.
NMR: described in the table below, (compound 13)
LC/MS: MH+ = 578
Example 4:
2-{2-(S)-[2-(S)-hydroxy(3,3-dimethyl)butyrylamino]-
pentanoyl}amino-5-(1-methylethyl)-4-(1,3-benzoxazol-
2-yl)thiazole (compound 34)

A solution of 3 g of 2-tert-butoxycarbonyl-
amino-5-(1-methylethyl)thiazole-4-carboxylic acid,
obtained in step 4.1, in 75 ml of dimethylformamide at
0°C is admixed with 1.2 g of N-methylmorpholine, 6.11 g
of PyBOP and then 1.3 g of 2-aminophenol. The reaction
mixture is allowed to return to ambient temperature and
is stirred for 16 h and then concentrated. The residue
is taken up in ethyl acetate and washed twice with
saturated aqueous sodium bicarbonate solution, twice
with water, once with a 1 M aqueous solution of

A solution of 2.72 g of 2-tert-butoxycarbonyl-
amino-5-(1-methylethyl)thiazole 4-(2-hydroxy)phenyl
carboxamide, obtained in step 4.2, in 8 0 ml of
tetrahydrofuran at 0°C is admixed with 2.1 g of
triphenylphosphine and then, dropwise, with 1.86 g of
DIAD in 3 0 ml of tetrahydrofuran. The reaction mixture
is slowly allowed to return to ambient temperature and
is stirred for 16 h and then concentrated. The residue

17.42 g of methyl 3-methoxyacrylate are
dissolved in 200 ml of a 1/1 1,4-dioxane/water mixture
and the solution is cooled to 0°C before 2 9.37 g of
N-bromosuccinimide are added. After 1 h at 0°C 11.42 g
of thiourea are added and then the mixture is heated at
80°C for 2 hours. The reaction mixture is subsequently
evaporated and the residue is taken up in ethyl acetate
and then washed twice with 10% aqueous sodium hydroxide
solution and then with saturated sodium chloride
solution. The organic phase is dried over anhydrous
magnesium sulphate and then concentrated.
This gives 19.17 g of a beige solid.
LC/MS: MH+ = 159

The amine of this intermediate is subsequently
protected by a Boc group according to the process
described in step 1.2 of Example 1. The mass of product
obtained is 30.7 g.
LC/MS: MH+ = 259
NMR 300 MHz (CDCl3) δ ppm: 1.50 (s,9H); 3.80 (s,3H);
8.06 (s,1H).
Example 5.2:
2-tert-butoxycarbonylaminothiazole 5-benzylamide

Starting from the methyl 2-tert-butoxy-
carbonylaminothiazole-5-carboxylate obtained in step
5.1 the corresponding acid is prepared as described in
step 2.3 of Example 2. Starting from the 2-tert-
butoxycarbonylaminothiazole-5-carboxylic acid thus
obtained the amide (4.35 g) is prepared as described in
Example 2.4.
LC/MS: MH+ = 334.

Example 5.3:
2-tert-butoxycarbonylamino-5- (1 -benzyl-1H-tetrazol-
5-yl)thiazole
A solution of 4.35 g of the compound obtained
in step 5.2 in 200 ml of tetrahydrofuran at 0°C is
admixed with 10.3 g of triphenylphosphine and then,
dropwise, with 7.92 g of DIAD in 30 ml of tetrahydro-
furan. After 15 minutes 4.5 g of azidotrimethylsilane,
diluted in 2 0 ml of tetrahydrofuran, are added. The
reaction mixture is allowed to return to ambient
temperature and is stirred for 24 h and then
concentrated. The residue is taken up in ethyl acetate
and the precipitate formed is filtered off and then
chromatographed on a silica gel column, eluting with a
5:5 (v/v) mixture of petroleum ether and ethyl acetate.
This gives 4 g of an orange-coloured oil which is
rechromatographed on a silica gel column with a mixture
of dichloromethane and ethyl acetate going from 10:0
(8:2) (v/v).
LC/MS: MH+ = 359.
NMR 300 MHz (CDCl3) δ ppm: 1.50 (s,9H); 5.92 (s,2H);
7.18 (m,2H); 7.37 (m,3H); 7.98 (s,1H); 8.86 (s,1H).

Example 5.4:
2-{2-(S)-[2-(S)-hydroxy (3,3-dimethyl)butyrylamino]-
pentanoyl}amino-5-(1-benzyl-1H-tetrazol-5-yl)thiazole
The 2-tert-butoxycarbonylamino-5-(1-benzyl-
1H-tetrazol-5-yl)thiazole obtained in step 5.3 is
subsequently deprotected with trifluoroacetic acid as
described in step 1.3 of Example 1, then two successive
couplings are carried out according to the processes
described in steps 1.4 and 1.5 of Example 1.
This gives 0.090 g of end product.
NMR: described in the table below, (compound 51)
LC/MS: MH+ = 472.6
Example 6:
2-{2- (S) - [2- (3,5-difluoropheny)acetylamino] -
pentanoyl}amino-4-methylthiazole 5-(N-2,3-dichloro-
benzyl)sulphonamide (compound 64)

Example 6.2:
2-amino-4-methylthiazole 5- (N-2,3-dichlorobenzyl)-
sulphonamide
2.4 g of 2-acetamido-4-methylthiazole
5-(N-2,3-dichlorobenzyl)sulphonamide, obtained in step
6.1, in 100 ml of a 2 N HC1 solution are heated at
100°C for 6 h. The contents of the round-bottomed flask
are evaporated and then the residue is taken up in
dichloromethane. It is washed three times with 20%
sodium carbonate solution and the organic phase is
dried over anhydrous magnesium sulphate. Filtration and
evaporation give 2 g of white powder.
NMR 300 MHz (DMSO) δ ppm: 2.24 (s,3H); 4.02 (d,2H);
7.31-7.60 (m,3H); 7.69 (s,2H); 8.28 (t,1H).
Example 6.3:
2-{2-(S)-[2-(3,5-difluorophenyl)acetylamino]-
pentanoyl}amino-4-methylthiazole 5-(N-2,3-dichloro-
benzyl ) sulphonamide
Starting from the 2-amino-4-methylthiazole
5-(N-2,3-dichlorobenzyl)sulphonamide obtained in step
6.2, 2 successive couplings are carried out according
to the processes described in steps 1.4 and 1.5 of
Example 1.

This gives 0.42 g of end product.
NMR: described in the table below, (compound 64)
LC/MS: MH+ = 605
The table which follows illustrates the
chemical structures and physical properties of some
examples of compounds according to the invention.

In the table:
- (S) or (R) in the columns "R3" and "R2, R'2"
indicates the stereochemistry of the asymmetric carbon
carrying R3 or R2 in the formula (I) . For the carbon
carrying R2 the indication (S) or (R) does not relate to
the case where R2 and R'2 together form an oxo group;
- MH+ is the value of the mass of the compound
protonated by a hydrogen atom (mass of the compound +
1), as determined by LC-MS.
The compounds of the invention were subjected
to pharmacological tests, which showed their advantage
as active substances in therapy.
They were tested in particular for their
inhibitory effects on the production of the β-amyloid
peptide (β-A4).
β-Amyloid peptide (β-A4) is a fragment of a
larger precursor protein called APP (amyloid precursor
protein). The latter is produced and is present in
various cells of human or animal tissue. However its
cleavage in cerebral tissue by protease-type enzymes
leads to the formation of the β-A4 peptide, which
accumulates in the form of an amyloid plaque. The two
proteases responsible for producing the amyloid peptide
are known by the name of beta- and gamma-secretases
(Wolfe MS, Secretase targets for Alzheimer's disease:
identification and therapeutic potential, J. Med. Chem.
2001, 44 (13): 2039-60).

It has been demonstrated that this gradual
deposition of the β-A4 peptide is neurotoxic and might
play an important role in Alzheimer's disease.
Accordingly the compounds of the present
invention, as an inhibitor of the production of the
p-amyloid peptide (β-A4) by inhibition of gamma-
secretase, can be used in the treatment of pathologies
such as senile dementia, Alzheimer's disease, Down's
syndrome, Parkinson's disease, amyloid angiopathy
and/or cerebrovascular disorders, frontotemporal
dementias and Pick's disease, post-traumatic dementias,
pathologies linked to neuroinflammatory processes,
Huntington's disease and Korsakov's syndrome.
The tests were conducted in accordance with
the protocol described below.
For the β-amyloid cellular test, the CHO-K1
line coexpres3ing the CT100 of APP and PS1 M146L clone
3O-12 is used. The line targets the inhibition of
gamma-secretase. Presenilin is linked to gamma-
secretase activity (Wolfe MS, Haass C, The Role of
presenilins in gamma-secretase activity, J. Biol. Chem.
2001, 276(8): 5413-6) and its coexpression with the
amyloid protein or its N-terminal fragment causes an
increase in secretion of the peptide Al-42 (β-A4),
thereby generating a pharmacological tool which allows
inhibition by the compounds of formula (I) of the
production of the β-A4 peptide to be evaluated. 96-well
culture plates are inoculated with 1x105 cells per well

in 150 µl of incubation medium. The presence of a
minimum percentage (1.3% final) of serum allows
cellular adhesion to the plastic after 2-3 hours of
incubation at 37°C, in the presence of 5% CO2. The
products (15 µl) are tested at 10 µM DMSO 1% final and
are incubated for 24-25 h at 37°C in the presence of 5%
CO2 and 100% humidity. After this 24-25 h incubation,
the cellular supernatants (100 µl) are transferred to
ELISA plates, treated with the capture antibody 6E10
(6E10, epitope: aal-17, INTERCHIM/SENETEK 320/10), to
determine the amount of amyloid peptides secreted by
the cells in the presence of compounds according to the
invention. A series of synthetic control peptide,
"peptide 1-40", at 5 and 10 ng/ml is treated in
parallel. The ELISA plates are incubated overnight at
4°C.
The quantity of bound peptide is detected
indirectly in the presence of a competitor which
corresponds to the truncated peptide, peptide 1-28
coupled to biotin, which is then detected with
streptavidin coupled to alkaline phosphatase. The
substrate, p-nitrophenyl phosphate (pNPP FAST
p-Nitrophenyl Phosphate, Sigma N2770), gives a yellow,
soluble reaction product which can be read at 405 nm.
The reaction is stopped with 0.1 M EDTA solution. For
this purpose, following binding of the amyloid peptide
in the ELISA plate, 50 µl of biotinylated peptide 1-28
are added to 100 µl of cellular supernatant and

incubated for 3 0 minutes at ambient temperature. The
ELISA plates are then washed 3 times. After drying by-
inversion on absorbent paper, 100 µl of streptavidin-
alkaline phosphatase (Interchim/Jackson ImmunoResearch
Laboratories 016-05O-084) are added per well and
incubated for 1 hour at ambient temperature. The plates
are washed again and then the alkaline phosphatase
substrate (pNPP 1 mg/ml) is added in an amount of
100 µl per well. After 30 minutes of incubation at
ambient temperature the reaction is stopped by adding
100 µl per well of 0.1 M EDTA and reading is carried
out at 405 nm.
The most active compounds of formula (I)
according to the present invention showed an EC50 (50%
effective concentration) of less than 500 nM, more
particularly less than 100 nM.
Table 2 below gives the EC50 values of several
compounds according to the invention.

The results of biological tests show that the
compounds are inhibitors of the formation of the
(β-amyloid peptide (β-A4) .

Accordingly these compounds can be employed
in the treatment of pathologies in which a β-amyloid
peptide (p-A4) formation inhibitor provides a
therapeutic benefit. Particular such pathologies are
senile dementia, Alzheimer's disease, Down's syndrome,
Parkinson's disease, amyloid angiopathy,
cerebrovascular disorders, frontotemporal dementias and
Pick's disease, post-traumatic dementias, pathologies
linked to neuroinflammatory processes, Huntington's
disease and Korsakov's syndrome.
The use of the compounds according to the
invention for preparing a medicinal product intended
for treating the abovementioned pathologies forms an
integral part of the invention.
The invention further provides medicinal
products which comprise a compound of formula (I), or
an addition salt thereof with a pharmaceutically
acceptable acid or else a hydrate or a solvate of the
compound of formula (I). These medicinal products find
their use in therapy, in particular in the treatment of
the abovementioned pathologies.
In another of its aspects the present
invention relates to pharmaceutical compositions
comprising as active principle at least one compound
according to the invention. These pharmaceutical
compositions comprise an effective dose of a compound
according to the invention, or of a pharmaceutically
acceptable salt, hydrate or solvate of the said

compound, and, optionally, one or more pharmaceutically
acceptable excipients.
The said excipients are selected, according to the
pharmaceutical form and the desired mode of
administration, from the customary excipients which are
known to the person skilled in the art.
In the pharmaceutical compositions of the
present invention for oral, sublingual, subcutaneous,
intramuscular, intravenous, topical, local,
intratracheal, intranasal, transdermal or rectal
administration, the active principle of formula (I)
above, or its salt, its solvate or its hydrate where
appropriate, can be administered in unit form for
administration, as a mixture with conventional
pharmaceutical excipients, to animals and to humans for
the prophylaxis or treatment of the above diseases or
disorders.
The appropriate unit forms for administration
embrace the forms for oral administration such as
tablets, soft or hard gelatin capsules, powders,
granules, chewing gums and oral solutions or
suspensions, the forms for sublingual, buccal,
intratracheal, intraocular or intranasal administration
or for administration by inhalation, the forms for
subcutaneous, intramuscular or intravenous
administration and the forms for rectal or vaginal
administration. For topical application the compounds

according to the invention can be used in creams,
ointments or lotions.
By way of example, a unit form for
administration of a compound according to the invention
in tablet form may comprise the following components:
Compound according to the invention 50.0 mg
Mannitol 223.75 mg
Croscaramellose sodium 6.0 mg
Maize starch 15.0 mg
Hydroxypropylmethylcellulose 2.25 mg
Magnesium stearate 3.0 mg
In order to obtain the desired therapeutic or
prophylactic effect, the dose of active principle may
vary between 0.1 mg and 200 mg per kg of body weight
per day. Although these dosages are average-situation
examples, there may be particular cases in which higher
or lower dosages are appropriate: such dosages are
likewise part of the invention. In accordance with
customary practice, the dosage appropriate to each
patient is determined by the doctor in accordance with
the mode of administration, the weight and the response
of the said patient.
Each unit dose can contain from 0.1 to
1000 mg, preferably from 0.1 to 500 mg, of active
principle in combination with one or more
pharmaceutical excipients. This unit dose can be
administered from 1 to 5 times per day, in order to

administer a daily dosage of from 0.5 to 5000 mg,
preferably from 0.5 to 2500 mg.
In another of its aspects the present
invention likewise relates to a method of treating the
pathologies indicated above which comprises
administering a compound according to the invention, a
pharmaceutically acceptable salt or a hydrate of the
said compound.

We Claim:
1. Compound conforming to the general
formula (.1) :
in which
R1 represents either a C1-6 alkyl optionally substituted
by one to three substituents selected from a halogen, a
trifluoromethyl, a hydroxyl, a C1-6 alkoxy, a C1-6
thioalkyl, a thiophene or a phenyl; or a C3-7 cycloalkyl,
a thiophene, a benzothiophene, a pyridinyl, a furanyl
or a phenyl; the said phenyl groups- being, optionally
substituted by one to three substituents selected from
a halogen atom, a C1-6 alkyl, a C1-6 alkoxy, a hydroxyl, a
methylenedioxy, a phenoxy, a benzyloxy or a
trifluoromethyl;
R2 and R'2 represent independently of 'one another 'a
hydrogen atom, a halogen atom, a hydroxyl; a C1-3
alkoxy, a C1-3 alkyl, a C3-7 cycloalkyl or an O-C(O)-C1-6
alkyl group, or R2 and R'2 together form an oxo group;
R3 represents either a hydrogen atom or a C1-6 ' alkyl
optionally substituted by a hydroxyl, a C1-6 cycloalkyl
or a C1-3 alkoxy;
R4 is Z and R5 is a hydrogen atom, a C1-7 alkyl, a trifluoromethyl,
a group L or a group Z; or
R4 is L and R5 is Z,

G represents a C1-7 alkyl or a single bond;
M represents a C3-7, cycloalkyl, a phenyl, a naphthyl or
a .pyridinyl, the group M being optionally substituted
by one or more groups selected from a halogen atom, a
hydroxyl group, a C1-3 alkyl, a C1-3 alkoxy, a
trifluoromethyl, a trifluoromethoxy and a -O-CHF2;
J represents a hydrogen atom or a group -Y-K;
Y represents a single bond, an oxygen or sulphur atom,
a -C1-4 alkylene-, -O-C1-4 alkylene- or -C1-4 alkylene-O-
group or a group -N(W)-, the -C1-4 alkylene- group being
optionally substituted by a hydroxyl or C1-3 alkoxy
group;
W represents either a hydrogen atom, or a C1-3 alkyl
optionally substituted by a phenyl, or a phenyl;
K represents a phenyl or pyridinyl group, the group K
being optionally substituted by one or more groups
selected from a halogen atom, a hydroxyl group, a C1-3
alkyl, a C1-3 alkoxy, a trifluoromethyl, a trifluoro-
methoxy and an -O-CHF2;
Z represents a heteroaromatic group, the said
heteroaromatic group being optionally substituted by a

group R8; R8 representing either a C1-4 alkyl which is
itself optionally substituted by a CN, a phenyl or a
phenoxy; or a phenyl; the said phenyl and phenoxy
groups being optionally substituted by 1 to 3 groups
selected from a halogen atom, a C1-3 alkyl, a C1-3 alkoxy
and a trifluoromethyl;
in the form of a base, addition salt with an acid,
hydrate or solvate.
2. Compound as claimed in claim 1,
wherein:
R1 represents a C1-6 alkyl or a phenyl which is
optionally substituted by 1 to 3 halogen atoms;
R2 and R'2 represent independently of one another a
hydrogen atom or a hydroxyl;
R3 represents a C1-6 alkyl;
R4 is Z and R5 is a hydrogen atom, a C1-7 alkyl, a
trifluoromethyl, a group L or a group Z; or
R4 is I and R5 is Z,

G represents a C1-7 alkyl or a single bond;
M represents a phenyl which is optionally substituted
by one or more halogen atoms;
J represents a hydrogen atom or a group -Y-K;
Y represents a single bond, an oxygen atom or
-O-C1-4 alkylene-;
K represents a phenyl group which is optionally
substituted by one or more groups selected from a
halogen atom, a C1-3 alkyl and a trifluoromethyl;
with the proviso that at least one group R4 or R5
represents a group Z;

Z represents a heteroaromatic group, the said heteroaromatic
group being optionally substituted by a group R8; R8 representing
either a C1-4 alkyl which is itself optionally substituted by a
phenyl; or a phenyl;
in the form of a base, addition salt with an acid,
hydrate or solvate.
3. Compound of formula (I) as claimed in
claim 1 or 2, wherein:
R1 represents a C1-4 alkyl, preferably an isopropyl or a
tert-butyl,or a phenyl substituted by two fluorine
atoms;
R2 and R'2 represent independently of one another a
hydrogen atom of a hydroxyl;
R3 represents a C1-4 alkyl, preferably a methyl, ethyl or
propyl;
in the form of a base, addition salt with an acid,
hydrate or solvate.
4. Process for preparing a compound of
formula (I) as claimed in any one of claims 1 to 3,
comprising the step consisting in
carrying out a peptide coupling of the 2-aminothia2ole
of formula (III)

with the acylamino acid of formula (II)

in which R1, R2, R'2 , R3, R4 and R5 are as defined in the
formula (I) as claimed in any one of Claims 1 to 3.
5. Process for preparing a compound of
formula (I) as claimed in any one of claims 1 to 3,
comprising the step consisting in
carrying out a peptide coupling of the compound of
formula (IV)
with the amine of formula (VI)

in which R1, R2/ R'2 ,R3, R4 and R5 are as defined in the
formula (I) as claimed in any one of Claims 1 to 3.
6. Medicinal product wherein, it comprises
a compound of formula (I) as claimed in any one of
Claims 1 to 3, in the form of a pharmaceutically
acceptable base, salt, hydrate or solvate.
7. Pharmaceutical composition comprising at
least one compound of formula (I) as claimed in any one

of Claims 1 to 3, in the form of a pharmaceutically
acceptable base, salt, hydrate or solvate, and
optionally one or more pharmaceutically acceptable
excipients.
8. A medicinal product as claimed in claim
6, for treating a pathology in which a β-A4 β-amyloid
peptide formation inhibitor provides a therapeutic
benefit.
9. A medicinal product as claimed in claim
6, for treating senile dementia, Alzheimer's disease,
Down's syndrome, Parkinson's disease, amyloid
angiopathy, cerebrovascular disorders, frontotemporal
dementias and Pick's disease, post-traumatic dementias,
pathologies linked to neuroinflammatory processes,
Huntington's disease and/or Korsakov's syndrome.

The invention relates to a compound
having general formula (I), wherein: R1 represents
either an optionally-substituted C1-6 alkyl or a
C3-7cycloalkyl, a thiophene, a benzothiophene, a
pyridinyl, a furanyl or a phenyl, said phenyl groups
being optionally substituted; R2 and R'2represent,
independently of each other, a hydrogen atom, a
halogen atom, a hydroxy, a C1-3 alkoxy, a C1-3 alkyl,
a C3-7 cycloalkyl, an O-C(O)-C1-6alkyl group, or R2
and R'2 together form an oxo group; R3 represents
either a hydrogen atom or an optionally-substituted
C1-6 alkyl; R4 and R5 represent, independently
G J of each other, a hydrogen atom, a C1-7 alkyl,
' M (L) a trifluoromethyl, an L group or a Z group; G
represents a C1-7 alkyl or a single bond; M represents
a C3-7 cycloalkyl, a phenyl, a naphtyl or a pyridinyl,
group M being optionally substituted; J represents a hydrogen atom or a group -Y-K; Y represents a single bond, an oxygen atom,
a sulphur atom, an optionally-substituted -C1-4alkylene- group, -O-C1-4 alkylene-, -C1-4 alkylene-O- or -N(W); K represents a
phenyl or pyridinyl group, group K being optionally substituted, with the proviso that at least one R4 or R5 group represents a Z
group; and Z represents a group CN, SO2NR6R7, or a heteroaromatic group, said heteroaromatic group being optionally substituted.
The inventive compound takes: the form of a base, an acid addition salt, a hydrate or a solvate. The invention also relates to the use
of said compound in therapeutics.